34584-69-5|3,6-Dichloro-4,5-dimethylpyridazine| Ambeed

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Quality Control of [ 34584-69-5 ] Purity: 98% SDS Specification

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Product Details of [ 34584-69-5 ]

CAS No. :	34584-69-5
Formula :	C₆H₆Cl₂N₂
M.W :	177.03
SMILES Code :	CC1=C(C)C(Cl)=NN=C1Cl
MDL No. :	MFCD00067745
InChI Key :	RUVVGCRPPJVNMC-UHFFFAOYSA-N
Pubchem ID :	21187505

Safety of [ 34584-69-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 34584-69-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.33
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	41.98
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	25.78 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.19
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.5
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.4
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.9
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.05
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.41

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.96
Solubility	0.196 mg/ml ; 0.00111 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.69
Solubility	0.364 mg/ml ; 0.00206 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.66
Solubility	0.0391 mg/ml ; 0.000221 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.6 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.01

Application In Synthesis of [ 34584-69-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 34584-69-5 ]

[ 34584-69-5 ] Synthesis Path-Downstream 1~35

1
[ 34584-69-5 ]
[ 38283-35-1 ]

References: [1]Journal of Organic Chemistry,1955,vol. 20,p. 707,708.

2
[ 110-91-8 ]
[ 34584-69-5 ]
[ 89937-29-1 ]

References: [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1077 - 1083.

3
[ 34584-69-5 ]
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-7,8-dimethyl-imidazo[1,2-<i>b</i>]pyridazine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 350 - 361.

4
[ 34584-69-5 ]
[ 328554-59-2 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 350 - 361.

5
[ 34584-69-5 ]
[ 89937-37-1 ]

References: [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1077 - 1083.

6
[ 34584-69-5 ]
[ 89937-43-9 ]

References: [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1077 - 1083.

7
[ 63751-07-5 ]
[ 34584-69-5 ]

References: [1]Journal of Organic Chemistry,1955,vol. 20,p. 707,708.

Yield	Reaction Conditions	Operation in experiment
		Preparation 5 Synthesis of 3-methoxy-4,5-dimethyl-6-chloropyridazine 0.46 g(0.02 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then 3.54 g(0.02 mol) of 3,6-dichloro-4,5-dimethylpyridazine obtained from Preparation 3 was added thereto and completely dissolved. The reaction solution was stirred for one hour at room temperature and concentrated under reduced pressure to remove excessive methanol. 100 ml of diethyl ether was added to the residue and then vigorously stirred for 10 minutes. The diethyl ether-insoluble materials were removed off and the remaining solution was washed two times with 50 ml of purified water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to remove diethyl ether. In this manner, the title compound was obtained as a white needle crystal. Yield: 2.63 g (76.2percent) Melting Point: 80-82° C. Recrystallizing solvent: ethanol
		Preparation 5 Synthesis of 3-methoxy-4,5-dimethyl-6-chloropyridazine 0.46g(0.02mol) of metallic sodium was dissolved in 30mlitre of absolute methanol and then 3.54g(0.02mol) of 3,6-dichloro-4,5-dimethylpyridazine obtained from Preparation 3 was added thereto and completely dissolved. The reaction solution was stirred for one hour at room temperature and concentrated under reduced pressure to remove excessive methanol. 100mlitre of diethyl ether was added to the residue and then vigorously stirred for 10 minutes. The diethyl ether-insoluble materials were removed off and the remaining solution was washed two times with 50mlitre of purified water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to remove diethyl ether. In this manner, the title compound was obtained as a white needle crystal, Yield: 2.63g (76.2percent) Melting Point: 80-82°C Recrystallizing solvent: ethanol

9
[ 34584-69-5 ]
3-methoxy-4,5-dimethyl-6-chloropyridazine [ No CAS ]
3-ethoxy-4,5-dimethyl-6-chloropyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol;	Preparation 8 Synthesis of 3-ethoxy-4,5-dimethyl-6-chloropyridazine 0.69 g(0.03 mol) of metallic sodium was dissolved in 100 ml of absolute ethanol and then 5.31 g(0.03 mol) of <strong>[34584-69-5]3,6-dichloro-4,5-dimethylpyridazine</strong> was added thereto and completely dissolved. The reaction solution was stirred for 4 hours at room temperature and then treated according to the same manner as Preparation 5 to obtain the title compound as a pale white crystal. Yield: 4.22 g (75.4percent) Melting Point: 60-62° C. Recrystallizing solvent: ethanol NMR(CDCl3, delta): 1.42(t, 3H, CH3), 2.20((s, 3H, CH3), 2.32(s, 3H, CH3), 4.52(q, 2H, OCH2)
	In ethanol;	Preparation 8 Synthesis of 3-ethoxy-4,5-dimethyl-6-chloropyridazine 0.69g(0.03mol) of metallic sodium was dissolved in 100mlitre of absolute ethanol and then 5.31g(0.03mol) of <strong>[34584-69-5]3,6-dichloro-4,5-dimethylpyridazine</strong> was added thereto and completely dissolved. The reaction solution was stirred for 4 hours at room temperature and then treated according to the same manner as Preparation 5 to obtain the title compound as a pale white crystal. Yield: 4.22g (75.4percent) Melting Point: 60-62°C Recrystallizing solvent: ethanol NMR(CDCl3, delta): 1.42(t, 3H, CH3), 2.20((s, 3H, CH3), 2.32(s, 3H, CH3), 4.52(q, 2H, OCH2)

References: [1]Patent: US5942511,1999,A .
[2]Patent: EP1058681,2003,B1 .

10
[ 34584-69-5 ]
[ 1013-22-5 ]
3-chloro-6-[4-(2,3-dimethylphenyl)-1-piperazinyl]-4,5-dimethylpyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2 parts (30%)	With potassium carbonate; In water;	Example 36 A mixture of 3.9 parts of <strong>[34584-69-5]3,6-dichloro-4,5-dimethylpyridazine</strong>, 4.2 parts of 1-(2,3-dimethylphenyl)piperazine and 2.94 parts of potassium carbonate was stirred and heated for 4 hours in an oil bath at 190° C. After cooling, the mixture was taken up in water and trichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2 parts (30percent) of 3-chloro-6-[4-(2,3-dimethylphenyl)-1-piperazinyl]-4,5-dimethylpyridazine; mp. 194.5° C. (compound 217).
2 parts (30%)	With potassium carbonate; In water;	Example 36 A mixture of 3.9 parts of <strong>[34584-69-5]3,6-dichloro-4,5-dimethylpyridazine</strong>, 4.2 parts of 1-(2,3-dimethylphenyl)piperazine and 2.94 parts of potassium carbonate was stirred and heated for 4 hours in an oil bath at 190°C. After cooling, the mixture was taken up in water and trichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2 parts (30percent) of 3-chloro-6-[4-(2,3-dimethylphenyl)-1-piperazinyl]-4,5-dimethylpyridazine; mp. 194.5°C (compound 217).

References: [1]Patent: US5001125,1991,A .
[2]Patent: EP156433,1991,B1 .

11
[ 34584-69-5 ]
[ 1032714-27-4 ]

Yield	Reaction Conditions	Operation in experiment
77%		Description 10; 3-Chloro-6-iodo-4,5-dimethyl-pyridazine (DlO); N - N A mixture of D9 (0.2 g, 1.13 mmol), sodium iodide (0.420 g, 2.8 mmol) and hydroiodic acid (57 wt.percent in water, 2 ml) was stirred at 120 0C for 10 min., under microwave irradiation. The mixture was then poured into an aqueous saturated solution of sodium carbonate, Na2S2O3, water and dichloromethane. The organic phase was separated, filtered over cotton, and the solvent evaporated in vacuo. The residue was purified by column chromatography (dichloromethane / heptane 1 :1 to 8:2) to yield DlO (0.235 g, 77percent) as a solid. C6H6CUN2 requires 268; Found 269 (MH+).

References: [1]Patent: WO2008/68277,2008,A1 .Location in patent: Page/Page column 21.

12
[ 5754-17-6 ]
[ 34584-69-5 ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 160℃; for 0.333333h;Microwave irradiation;	Description 9; 3,6-Dichloro-4,5-dimethyl-pyridazine (D9); A mixture of 6-hydroxy-4,5-dimethyl-2H-pyridazin-3-one (2.56 g, 18 mmol) (prepared by a procedure similar to that described in WO 99/36407), phosphorus oxychloride (8 ml) and diisopropylethylamine (4 ml) was stirred at 160 0C for 20 min., under microwave irradiation (Biotage MW-oven). The solvent was then partially evaporated in vacuo and remaining material poured into a mixture of cold water, saturated sodium hydrogen carbonate and dichloromethane. The mixture was then basified with portions of sodium hydrogen carbonate until there was no more CO2 evolution. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography (dichloromethane / heptane 1/1 to 10/0) to yield D9 (1.7 g, 53 percent) as a solid. C6H6Cl2N2 requires 176; Found 177 (MH+)

References: [1]Patent: WO2008/68277,2008,A1 .Location in patent: Page/Page column 21.

13
[ 34584-69-5 ]
[ 1057682-71-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 5h;Irradiation; Heating / reflux;	To a stirred solution of <strong>[34584-69-5]3,6-dichloro-4,5-dimethylpyridazine</strong> (500 mg, 2.82 mmol) in carbon tetrachloride (10 mL) was added nu-bromosuccinimide (503 mg, 2.82 mmol), and AIBnu (2.3 mg, 0.014 mmol) in a round bottom flask equipped with condenser. The reaction was continuously irradiated with a 300 W light and refluxed for 5 h. The formed succimide was filtered and the filtrate was concentrated to afford 4-(bromomethyl)-3,6- dichloro-5-methylpyridazine as a brown solid. To a solution of 4-(bromomethyl)-3,6- dichloro-5-methylpyridazine (400 mg, 1.56 mmol) in DMF was added with benzyl amine (188 muL, 1.72 mmol) and TEA (326 muL, 2.34 mmol). The reaction mixture was heated at 90 0C for 2 h, diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to afford a brown oil. The crude material was purified by flash chromatography on silica gel, eluting with 30 - 80percent EtOAc: heptane. Fractions containing the desired product were combined and concentrated to afford a the title compound as a greasy solid (430 mg, yield: 54percent (two steps)). MS (m/z, MH+): meas. 282.2 calc. 282.05

References: [1]Patent: WO2008/110611,2008,A1 .Location in patent: Page/Page column 106.

14
[ 34584-69-5 ]
[ 1057682-52-6 ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 16h;Irradiation; Heating / reflux;	To a stirred solution of <strong>[34584-69-5]3,6-dichloro-4,5-dimethylpyridazine</strong> (3 g, 16.9 mmol) in 56 mL carbon tetrachloride was added with N-bromosuccinimide (9.1 g, 50.8 mmol), and AIBN (27.8 mg, 0.17 mmol) in a round bottom flask equipped with a condenser. The reaction was continuously irradiated with a 300 W light and refluxed for 16 h. The formed succimide was filtered and the filtrate was concentrated to afford the crude material. The mixture was purified by flash chromatography on silica gel, eluting with 10 - 30percent EtOAc: heptane to afford a light yellow solid (3 g, yield: 53percent). <n="108"/>1H NMR (400MHz, CDCl3): 4.61 (s, 4 H) MS (m/z, MH+): meas. 335.0 calc. 334.8
11 g	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 16h;	Step a. To a solution of <strong>[34584-69-5]3,6-dichloro-4,5-dimethylpyridazine</strong> (CAS Number 34584-69-5, available from Accela chembio) (6 g, 33.9 mmol) in CC14 (150 ml) were added NBS (18.08 g, 101.6 mmol) and AIBN (0.055 g, 0.33 mmol) at rt. The reaction mixture was heated at 80°C for 16 h. The resulting reaction mixture was filtered and evaporated to yield 4,5-bis(bromomethyl)-3,6-dichloropyridazine (11 g, 32.8 mmol), LCMS: Method A, 2.102 min, MS: ES+ 335.18.

References: [1]Patent: WO2008/110611,2008,A1 .Location in patent: Page/Page column 106-107.
[2]Patent: WO2017/158388,2017,A1 .Location in patent: Page/Page column 109.

15
[ 34584-69-5 ]
[ 132834-58-3 ]
[ 1204977-19-4 ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 0.416667h;	1-(5-Trifluoromethyl-pyridin-2-yl)-piperazine (10 g, 43.3 mmol) is combined with <strong>[34584-69-5]3,6-dichloro-4,5-dimethyl-pyridazine</strong> (14.4 g, 84.3 mmol), triethylamine (8.25 mL), and NMP (40 mL). The reaction mixture is heated to a temperature of 180° C. for 25 min, and then concentrated in vacuo. The residue is purified by flash chromatography on silica gel (0-8percent MeOH/CH2Cl2) to afford the title compound (13.2 g, 82percent). 1H NMR (400 MHz, DMSO-d6) delta=8.48-8.41 (m, 1H) 7.84 (dd, J=9.1 Hz, 2.4 Hz, 1H) 7.03 (d, J=9.1 Hz, 1H) 3.88-3.76 (m, 4H) 3.28-3.20 (m, 4H) 2.31 (s, 6H).

References: [1]Patent: US2010/41663,2010,A1 .Location in patent: Page/Page column 19; 47.

16
[ 2739-97-1 ]
[ 34584-69-5 ]
[ 1204977-44-5 ]

Yield	Reaction Conditions	Operation in experiment
44%		3,6-Dichloro-4,5-dimethyl-pyridazine (1.00 g, 5.65 mmol) is added to a dry 250-ml round-bottom flask under N2 followed by THF (50 mL) and pyridin-2-yl-acetonitrile (800 mg, 7.68 mmol). The reaction is degassed for 30 min. NaHMDS (1.0 M, 14.13 mL, 14.13 mmol) is added and the reaction is stirred overnight. The reaction mixture is transferred to a beaker and air stirred vigorously for several hours. The reaction mixture is quenched with saturated sodium bicarbonate solution. The organics are extracted with dichloromethane. The combined organic layers are washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material is purified via flash chromatography on silica gel (0-20percent methanol in CH2Cl2) to afford the title compound (616 mg, 44percent). 1H NMR (400 MHz, DMSO-d6) delta=8.68 (m, 1H), 8.26 (m, 1H), 8.16 (m, 1H), 7.76 (m, 1H), 2.45 (s, 3H), 2.21 (s, 3H).

References: [1]Patent: US2010/41663,2010,A1 .Location in patent: Page/Page column 29.

17
[ 34584-69-5 ]
[ 75336-86-6 ]
[ 1204978-32-4 ]

Yield	Reaction Conditions	Operation in experiment
49%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 48h;	Solid K2CO3 (10 g, 72.4 mmol, 1.8 eq) is added to a solution of (R)-2-methyl-piperazine (4.00 g, 40 mmol, 1 eq) and <strong>[34584-69-5]3,6-dichloro-4,5-dimethyl-pyridazine</strong> (8 g, 45.2 mml, 1.1 eq) in DMF (50 mL), and the resulting solution is stirred at 60° C. for 48 h. The reaction mixture is concentrated to 1/2 volume under reduced pressure and the minimum water (ca. 15 mL) required to dissolve the solid salts is added, followed by the addition of dichloromethane (100 mL). The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure, then purified by silica gel column chromatography (2percent-20percent MeOH/CH2Cl2) to yield the desired compound as a white solid (4.7 g, 49percent).1H NMR (400 MHz, CDCl3) delta=3.08-3.21 (m, 2H), 2.73-2.92 (m, 4H,) 2.47 (dd, J=12.4 Hz, 10.2 Hz, 1H), 2.13 (s, 3H), 2.07 (s, 3H), 0.93 (d, J=6.3 Hz, 3H).HR MS (m/z, MH+): meas. 241.1218.

References: [1]Patent: US2010/41663,2010,A1 .Location in patent: Page/Page column 45.
[2]ChemMedChem,2013,vol. 8,p. 1261 - 1265.

18
[ 34584-69-5 ]
[ 75336-86-6 ]
[ 52334-81-3 ]
[ 1204978-49-3 ]

Yield	Reaction Conditions	Operation in experiment
37%		Combine <strong>[34584-69-5]3,6-dichloro-4,5-dimethyl-pyridazine</strong> (100 mg, 0.554 mmol), (R)-2-methylpiperazine (85 mg, 0.831 mmol), potassium carbonate (383 mg, 2.77 mmol) and DMF (1 mL) in vial. Heat in the microwave at 120° C. for 3.25 h. Add 2-chloro-5-trifluoromethylpyridine (181 mg, 0.997 mmol) and heat at 180° C. for 30 min. The crude reaction is purified directly by flash chromatography on silica gel (0-40percent EtOAc in heptanes) to afford the title compound as a light yellow solid (78 mg, 37percent).MS (m/z, MH+) meas. 386.4

References: [1]Patent: US2010/41663,2010,A1 .Location in patent: Page/Page column 46.

19
[ 6443-85-2 ]
[ 34584-69-5 ]
[ 1204977-41-2 ]

Yield	Reaction Conditions	Operation in experiment
93%		3,6-Dichloro-4,5-dimethyl-pyridazine (1.00 g, 5.65 mmol) is added to an oven-dried, 250-mL round-bottom flask under N2 followed by THF (50 mL) and pyridin-3-yl-acetonitrile (800 mg, 7.68 mmol). The reaction is degassed with a flow of N2 for 30 min. NaHMDS (14.13 mL, 1.0 M, 14.13 mmol) is added and the reaction is stirred for 16 h. The reaction mixture is then transferred to a beaker and stirred vigorously under open to the atmosphere for several hours. The reaction is quenched with saturated sodium bicarbonate solution, and the organics are extracted with dichloromethane. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material is purified via flash chromatography on silica gel (0-20percent methanol in CH2Cl2) to afford the title compound (1.3 g, 93percent). 1H NMR (400 MHz, DMSO-d6) delta=8.97 (s, 1H), 8.80 (d, J=4.5 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.60-7.64 (m, 1H), 2.44 (s, 3H), 2.33 (s, 3H).

References: [1]Patent: US2010/41663,2010,A1 .Location in patent: Page/Page column 29.

20
[ 34584-69-5 ]
[ 140-29-4 ]
[ 1204977-38-7 ]

Yield	Reaction Conditions	Operation in experiment
100%		3,6-Dichloro-4,5-dimethyl-pyridazine (1.00 g, 5.65 mmol) and phenyl acetonitrile (652 mL, 5.65 mmol) are dissolved in toluene (17.5 mL), cooled to 0° C. and charged with NaHMDS (5.65 mL, 2M in THF, 11.3 mmol). The reaction mixture is stirred for 16 h, slowly warming up from 0° C. to rt. The mixture is stirred vigorously at the open air for another 24 h. The mixture is quenched by the addition of aqueous NaHCO3 solution, the layers are separated and the aqueous phase is extracted with DCM. The combined organic phases are concentrated to give the title compound as a brown solid (1.4 g, quant.).1H NMR (400 MHz, CDCl3) delta=7.82 (m, 2H), 7.55 (m, 1H), 7.40 (m, 2H), 2.39 (s, 3H), 2.28 (s, 3H).MS (m/z, MH+) meas. 247.4.

References: [1]Patent: US2010/41663,2010,A1 .Location in patent: Page/Page column 28-29.

21
[ 34584-69-5 ]
[ 521985-03-5 ]
[ 1204978-67-5 ]

Yield	Reaction Conditions	Operation in experiment
43%	With triethylamine; In 1-methyl-pyrrolidin-2-one; at 190℃; for 1h;	To the solution of 3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5'-carboxylic acid methyl ester (250 mg, 1.07 mmol) in NMP (5 mL) is added <strong>[34584-69-5]3,6-dichloro-4,5-dimethyl-pyridazine</strong> (237 mg, 1.33 mmol) and TEA (446 mul, 3.21 mmol), the reaction mixture is stirred at 190° C. for 60 min. Water is added to the mixture and extracted with EtOAc. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by HPLC, (acetonitrile/water: 10percent95percent with 3percent 1-propanol) to give white powder (165 mg, 43percent).1H-NMR (400 MHz, DMSO-d6) delta=8.69 (s, 1H), 8.44 (s, 1H), 3.92 (t, J=5.0 Hz, 4H), 3.83 (s, 3H), 3.27 (m, 4H), 2.41 (s, 3H), 2.32 (s, 3H).MS (m/z, MH+) meas. 363.

References: [1]Patent: US2010/41663,2010,A1 .Location in patent: Page/Page column 48.

22
[ 34584-69-5 ]
[ 519059-09-7 ]
[ 959841-61-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1100 - 1105.

23
[ 34584-69-5 ]
[ 108612-54-0 ]
[ 1227070-23-6 ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 48h;	Preparation 1 tert-Butyl l-(6-chloro-4,5-dimethylpyridazin-3-yl)piperidin-4-yl(methyl)carbamate; Heat a mixture of <strong>[34584-69-5]3,6-dichloro-4,5-dimethylpyridazine</strong> (11.0 g, 62.1 mmol), tert- butyl methyl(piperidin-4-yl)carbamate (23.3 g, 109 mmol), and powdered K2CO3 (17.2 g, 124 mmol) in DMSO (310 mL) at 120 0C for 2 d. Cool the reaction mixture, dilute with H2O, and filter off the solid. Rinse the solid with H2O, and dry under vacuum at 45 0C. Dissolve the solid in CH2CI2, and pass the solution through a pad of silica gel, eluting with CH2CI2. Concentrate the organic layer under reduced pressure to obtain the title compound as a yellow solid (14.3 g, 65%). ES/MS m/z (35Cl) 355.0 (M+l).
30%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 5h;	tert-Butyl piperidin-4-ylmethylcarbamate (3.8i g, i 7.8mmol), <strong>[34584-69-5]3,6-dichloro-4,5-dimethyl-pyridazine</strong> (3.Og, i7.Ommol), NMP (i4mL) and N,N-Diisopropylethylamine (4.43mL, 25.4mmol) were added to a round bottom flask and heated to iSO C for 5 h. The mixture was partitioned between EtOAc (i 00 mL) and i M Na2003 aq. (50 mL). The organic layer was washed with i M Na2003 aq. (5OmL),water (2 x 7OmL), brine (70 mL), before passage through a hydrophobic frit and concentrated in vacuo to give an orange/brown solid. The crude material was purified by silica flash chromatography using 0% EtOAc in heptane with tn ethylamine i% with a gradient increasing to 30% ethyl actetate. Fractions containing product were combined and concentrated in vacuo to afford tert-butyl N-[i -(6-chloro-4,5-dimethyl-pyridazin-3-yl)-4-piperidyl]-N-methyl-carbamate(i .8g,5.i mmol, 30% yield).1H NMR (400MHz, ODd3) s/ppm: 4.34-3.84 (m, 2H), 3.56-3.47 (m(br), 2H), 3.00 (t(br), Ji2.OHz,2H), 2.78 (s, 3H), 2.3i (s, 3H), 2.25 (s, 3H), i .93-i .80 (m, 2H), i .78-i .7i (m(br), 2H), i .47 (s, 9H).MS Method 2: RT: i .88 mi m/z 355.9 [M÷H]÷

References: [1]Patent: WO2010/56588,2010,A1 .Location in patent: Page/Page column 9.
[2]Patent: WO2014/191737,2014,A1 .Location in patent: Paragraph 00235.

24
[ 34584-69-5 ]
[ 169447-70-5 ]
[ 1227064-25-6 ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; for 168h;	Heat a mixture of l,4-dichloro-2,3-dimethylpyridazine (6.06 g, 34.2 mmol), (S)-2- methyl-piperazine-1-carboxylic acid tert-butyl ester (6.88 g, 34.4 mmol) and dsopropylethylamine (30 ml, 172 mmol) in DMSO (30 mL) at 120 0C for 5 d. Cool and treat the mixture with additional (5)-2-methyl-piperazine-l-carboxylic acid tert-butyi ester (3.74 g, 18.7 mmol), and resume heating at 120 0C for an additional 2 d. Dilute the reaction mixture with EtOAc and wash with H2O and brine. Dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 20 to 50percent EtOAc in hexanes) to afford the title compound as a pale yellow foam (7.36 g, 63percent). ES/MS m/z (35Cl) 341.0 (M+l).

References: [1]Patent: WO2010/56620,2010,A1 .Location in patent: Page/Page column 8.

25
[ 34584-69-5 ]
[ 4152-09-4 ]
[ 1227064-32-5 ]